Heroin and related opioids are highly addictive drugs known for their analgesic properties. Since 2006, the number of heroin users in the United States has skyrocketed, reaching epidemic levels. Abuse of prescription opioid pain relievers oxycodone (Oxycotin) and hydrocodone (Vicodin) which are known gateway drugs to heroin has also increased dramatically. Because opioids present a significant abuse liability, new therapies are needed to combat the rapid rise in opioid dependence, especially since traditional pharmacological treatments such as methadone fall short at preventing relapse. Immunotherapy, in the form of a conjugate vaccine, is a promising new therapy for opioid addiction. In previous work, we demonstrated that a heroin-keyhole limpet hemocyanin (KLH) conjugate formulated with alum adjuvant generated a high titer antibody response against heroin in mice and rats. Moreover, in rodents we showed that anti-opioid antibodies elicited by this vaccine bound heroin and its metabolites in the blood with high specificity and affinity, thus safely mitigating the psychoactive effects of heroin without binding to endogenous receptors. As a result, our heroin vaccine was able to block heroin self-administration of dependent rats in many addiction models including conditioned-place preference, reinstatement and reacquisition. Dose-response heroin analgesia testing in mice revealed that this vaccine was able to shift EC50 of heroin 5-fold, however, we have since improved our vaccine to produce a massive >20-fold heroin EC50 shift. Furthermore, we tested the long-term performance of our optimized vaccine showing that it retains heroin immunoantagonism up to 2.5 months post-vaccination. Our studies have indicated that this heroin vaccine is safe, effective and long-lasting. The highly promising nature of our vaccine for treating heroin addiction warrants further preclinical development. In this STTR Fast Track application, we propose to select a lead heroin vaccine candidate for advancement to clinical evaluation and conduct the IND- enabling activities necessary to initiate clinical studies.